Activation of GPR44 decreases severity of myeloid leukemia via specific targeting of leukemia initiating stem cells

Fenghua Qian; Shaneice K Nettleford; Jiayan Zhou; Brooke E Arner; Molly A Hall; Arati Sharma; Charyguly Annageldiyev; Randy M Rossi; Diwakar B Tukaramrao; Deborpita Sarkar; Shailaja Hegde; Ujjawal H Gandhi; Emily R Finch; Laura Goodfield; Michael D Quickel; David F Claxton; Robert F Paulson; K Sandeep Prabhu

doi:10.1016/j.celrep.2023.112794

Activation of GPR44 decreases severity of myeloid leukemia via specific targeting of leukemia initiating stem cells

Cell Rep. 2023 Jul 25;42(7):112794. doi: 10.1016/j.celrep.2023.112794. Epub 2023 Jul 18.

Authors

Fenghua Qian¹, Shaneice K Nettleford¹, Jiayan Zhou¹, Brooke E Arner¹, Molly A Hall¹, Arati Sharma², Charyguly Annageldiyev², Randy M Rossi³, Diwakar B Tukaramrao², Deborpita Sarkar¹, Shailaja Hegde⁴, Ujjawal H Gandhi⁵, Emily R Finch⁶, Laura Goodfield⁷, Michael D Quickel¹, David F Claxton², Robert F Paulson⁸, K Sandeep Prabhu⁹

Affiliations

¹ Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, USA.
² Department of Medicine, Division of Hematology and Oncology, Penn State Cancer Institute, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
³ Transgenic Core Facility, Huck Institute of the Life Sciences, The Pennsylvania State University, University Park, PA 16802, USA.
⁴ Hoxworth Blood Center, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
⁵ Department of Hematology and Oncology, University of North Carolina Health, Cary, NC 27518, USA.
⁶ Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
⁷ Immunooncology Division, Bicycle Therapeutics, Boston, MA 02140, USA.
⁸ Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, USA. Electronic address: rfp5@psu.edu.
⁹ Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, USA. Electronic address: ksp4@psu.edu.

Abstract

Relapse of acute myeloid leukemia (AML) remains a significant concern due to persistent leukemia-initiating stem cells (LICs) that are typically not targeted by most existing therapies. Using a murine AML model, human AML cell lines, and patient samples, we show that AML LICs are sensitive to endogenous and exogenous cyclopentenone prostaglandin-J (CyPG), Δ¹²-PGJ₂, and 15d-PGJ₂, which are increased upon dietary selenium supplementation via the cyclooxygenase-hematopoietic PGD synthase pathway. CyPGs are endogenous ligands for peroxisome proliferator-activated receptor gamma and GPR44 (CRTH2; PTGDR2). Deletion of GPR44 in a mouse model of AML exacerbated the disease suggesting that GPR44 activation mediates selenium-mediated apoptosis of LICs. Transcriptomic analysis of GPR44^-/- LICs indicated that GPR44 activation by CyPGs suppressed KRAS-mediated MAPK and PI3K/AKT/mTOR signaling pathways, to enhance apoptosis. Our studies show the role of GPR44, providing mechanistic underpinnings of the chemopreventive and chemotherapeutic properties of selenium and CyPGs in AML.

Keywords: CP: Cancer; CRTH2; KRAS; MAP kinase; PPAR; RTK; leukemia; p53; prostaglandins; selenium.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line
Humans
Leukemia, Myeloid, Acute*
Mice
Phosphatidylinositol 3-Kinases
Selenium*
Signal Transduction

Substances

Phosphatidylinositol 3-Kinases
Selenium

Abstract

Publication types

MeSH terms

Substances

Grants and funding